AU-rich elements (AREs) are critical regulators of cytokine and proto-oncogene messenger RNAs, preventing aberrant inflammation and uncontrolled growth. The protein Nup475 (also known at tristetraprolin and TIS11) is the prototype of a family of ARE-binding proteins with a common structural motif, the Cys3His domain, which we have proven has a novel structure distinct from the classical zinc finger. Nup475 destabilizes mRNAs by deadenylation of the polyA tail, as well as with effects on transcriptional activation and to promote apoptosis. This proposal will define determinants of Nup475 binding and potential mechanisms for its action, including the role of this protein in a mouse model of inflammatory bowel disease.